Crystallization is a convenient, effective technique for purifying organic compounds. Purification by crystallization generally involves dissolving an impure substance in a solvent, removing insoluble impurities by filtering the solution and then precipitating the desired compound from the solution. Most soluble impurities are excluded from the growing crystals as the compound crystallizes. Ideally, soluble impurities remain in solution and are separated from the crystals by separating the solvent and washing the crystals.
Bulk producers of small organic molecules like pharmaceuticals endeavor to develop optimal crystallization techniques and thereby avoid less convenient purification techniques like chromatography.
Molecules of the solvent used in the crystallization, which are usually low volume, low molecular weight species, sometimes become incorporated into crystals during crystallization. Large, highly branched molecules are especially prone to this phenomenon. Solid materials that are obtained when molecules of a compound (hereafter referred to as the “host” compound) co-crystallize with a solvent (or “guest”) are called “solvates.” In some solvates, molecules of the host compound and guest are incorporated into the crystal in a fixed stoichiometric ratio. Some workers in the field of solid state chemistry and materials science reserve the term “solvate” for crystals whose ratio of host to guest is non-variable. In this disclosure, the term is used in the more broad sense in which it is understood in these fields to refer to any crystalline substance in which solvent is incorporated into the crystal lattice. In some solvates, the ratio of host compound to the guest is variable. In such solvates, the amount of solvent incorporated into the crystal can depend upon the specific crystallization procedure used to obtain the material and the conditions under which the material is maintained, such as the temperature and pressure. Solvates may be mixed. In other words, a crystal may contain more than one type of guest molecule in the crystal lattice. It is particularly relevant to this invention that a crystal can be a solvate of water (known as a hydrate) and an organic solvent.
Turning to other relevant background information relating to this invention, atorvastatin is the trivial name of ([R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid. Atorvastatin is administered to patients at risk for heart disease to lower their low density lipoprotein levels. Atorvastatin can be safely administered orally as a hemi-calcium salt. The crystalline form of atorvastatin hemi-calcium that has been approved by United States Food and Drug Administration for medical use is a trihydrate.
Although there is a general interest among chemical manufacturers in doing chemical synthesis in water for environmental reasons, as yet, atorvastatin has not been synthesized and crystallized using only reactions conducted in water. When conducting a synthesis in purely aqueous solvents is impracticable, lower alcohol solvents are a favorable alternative because they are able to dissolve substances of low polarity that do not dissolve in water, their toxicity is low compared to many other organic solvents, their cost is low and their solubility in water is high, which allows continuous variation of the properties of the solvent system by varying the ratio of alcohol and water, which can occur over a wide range.
U.S. Pat. No. 5,273,995 describes a preparation of atorvastatin hemi-calcium in which the atorvastatin lactone is dissolved in a mixture of methanol and water. A little less than one equivalent of sodium hydroxide is added to the solution until the lactone has been opened as determined by high performance liquid chromatography (HPLC). Then, one equivalent or a slight excess of calcium chloride dihydrate (CaCl2.2H2O) is added at elevated temperature. After completing the addition, atorvastatin hemi-calcium is obtained as a precipitate by cooling the solution.
U.S. Pat. No. 5,298,627 discloses another process for preparing atorvastatin hemi-calcium. First, atorvastatin sodium is produced from an N,N-diphenyl amide analog of atorvastatin without intermediate isolation of the lactone by treating the amide with sodium hydroxide in a mixture of methanol and water. Following workup, an aqueous layer containing methanol and atorvastatin sodium is obtained. An aqueous solution of calcium acetate (Ca(OAc)2) is then added to this aqueous layer at room temperature and the hemi-calcium salt is then precipitated by cooling.
U.S. Pat. No. 5,969,156 discloses atorvastatin hemi-calcium crystalline Forms I, II and III. According to the three examples in the '156 patent, each of these crystalline forms is obtained from a solution of methanol and water. In Example 1, a solution of atorvastatin sodium in a methanol and water mixture is treated with a solution of calcium acetate hemihydrate in water. After seeding with a crystal of Form I, followed by heating to 51–57° C. for at least ten minutes and then cooling to 15–40° C., a precipitate is filtered off, washed with ethanol and water and dried at 60–70° C. under vacuum for 4 days to give “Form I atorvastatin” (presumably the hemi-calcium salt). In Example 2, Form II is said to result by suspending Form I in a mixture of methanol and water. In Example 3, Form IV is said to result by following generally the procedure for producing Form I but with certain variations. Form IV also is obtained by precipitation from a mixture of methanol and water.
U.S. Pat. No. 6,121,461 describes atorvastatin hemi-calcium Form III which, according to Example 3 of the '461 patent, can be prepared by exposing atorvastatin hemi-calcium Form II to 95% relative humidity for eleven days.
Commonly assigned, co-pending U.S. Patent Application Publication No. 2002/0183378 discloses crystalline Forms VI, VIII–XII of atorvastatin hemi-calcium. Some of the forms are accessible by contacting atorvastatin hemi-calcium with mixtures of water and a lower alcohol, while others are accessible by other processes. In particular, atorvastatin hemi-calcium Form VI is obtained from a mixture of acetone and water. Atorvastatin hemi-calcium Form VII is obtained by treating certain atorvastatin hemi-calcium polymorphs with ethanol, preferably absolute ethanol with a low water content.
Atorvastatin hemi-calcium Form VIII is prepared under controlled conditions by a variety of procedures, some of which involve contacting atorvastatin hemi-calcium with mixtures of lower alcohols and water. In our hands and on our instrumentation, Form VIII produced a powder X-ray diffraction pattern with peaks at 6.9, 9.3, 9.6, 16.3, 17.1, 19.2, 20.0, 21.6, 22.4, 23,9, 24.7, 25.6, and 26.5±0.2 degrees 2θ. Form VIII has a monoclinic unit cell with lattice dimensions: a=18.55–18.7 Å, b=5.52–5.53 Å, c=31.0–31.2 Å and angle β between the a and c axes of 97.5–99.5°. Form VIII produced a solid-state cross-polarized/magic angle spinning (“CP/MAS”) 13C nuclear magnetic resonance spectrum with resonances at shift positions of about 17.8, 20.0, 24.8, 25.2, 26.1, 40.3, 40.8, 41.5, 43.4, 44.1, 46.1, 70.8, 73.3, 114.1, 116.0, 119.5, 120.1, 121.8, 122.8, 126.6, 128.8, 129.2, 134.2, 135.1, 137.0, 138.3, 139.8, 159.8, 166.4, 178.8, 186.5 ppm. Obtaining CP/MAS 13C NMR spectra with reproducible chemical shift positions can be difficult due to the need for an external standard. Chemical shift differences do not suffer from this problem. For atorvastatin hemi-calcium Form VIII, the shift differences between the lowest ppm resonance and the other resonances are: 2.2, 7.0, 7.4, 8.3, 22.5, 23.0, 23.7, 25.6, 26.3, 28.3, 53.0, 55.5, 96.3, 98.2, 101.7, 102.3, 104.0, 105.0, 108.8, 111.0, 111.4, 116.4, 117.3, 119.2, 120.5, 122.0, 142.0, 148.6, 161.0 and 168.7 ppm.
Further, according to the '378 publication, atorvastatin hemi-calcium Form IX can be obtained from heterogeneous mixtures of atorvastatin hemi-calcium and a diluent containing a lower alcohol and water. Atorvastatin hemi-calcium Form X can be prepared by reprecipitating certain crystalline forms of atorvastatin hemi-calcium from mixtures of ethanol and water. Atorvastatin hemi-calcium Form XI is obtained from a gel formed of atorvastatin hemi-calcium and isopropyl alcohol. Atorvastatin hemi-calcium Form XII is obtained after performing a functional group deprotection of an atorvastatin precursor in aqueous solvent.
Thus, it will be appreciated that mixtures of water and organic solvents, especially lower alcohols, are used extensively in the preparation of atorvastatin and its isolation as a hemi-calcium salt. When atorvastatin hemi-calcium is crystallized from mixtures of water and a lower alcohol as taught in the '995, '627 and '156 patents, and the '378 publication, it tends to form a mixed solvate with water and the lower alcohol. We have found that atorvastatin hemi-calcium obtained by crystallization from solvent systems containing lower alcohols like methanol, ethanol and butan-1-ol may contain from about 1% up to about 5% by weight of the alcohol in their crystal structure.
Some solvates can be desolvated by heating them and/or by placing them in a container that is maintained under positive vacuum. Depending on the host molecule and the particle size of the material, the ease of solvent release by heating and/or application of a vacuum may be facile, futile or somewhere in between. In many cases the desolvation requires heating to a temperature that produces an adverse effect on the quality of the product, both chemical and physical (which is the case with atorvastatin hemi-calcium). In addition, when the starting material is a mixed solvate and the desired product is a solvate of one of the solvent molecules initially present, heating and/or exposure to vacuum must selectively remove only the undesired solvent to be successful.
Where heating and reduced pressure fail, sometimes more exotic techniques will succeed at removing an undesirable solvent molecule from a mixed solvate. U.S. Pat. No. 6,080,759 describes a process for removing organic solvent from (−)-trans-4-(4′-fluorophenyl)-3-(3′, 4′-methenedioxyphenoxymethyl)-piperidine (paroxetine hydrochloride) by displacement with water. In the examples of the '759 patent, paroxetine hydrochloride containing any of a variety of organic solvents was stirred in liquid water to reduce the amount of organic solvent. For instance, in Example 1, paroxetine hydrochloride containing 13% propan-2-ol was stirred in a beaker with water for twenty minutes and then separated and dried. This caused a recrystallization of the paroxetine hydrochloride in anhydrous Form A. The '759 technique of displacement with liquid water appears to have general applicability with paroxetine hydrochloride since the examples show that paroxetine can be desolvated of a wide variety of organic solvents by that technique. However, a technique that is general in the sense that it can be used to remove a variety of solvents from crystals of a host compound does not necessarily mean it is applicable to a different host compound. Indeed, in the study of crystals, the results obtained by manipulating a material are frequently counterintuitive. For example, U.S. Pat. No. 6,002,011 discloses a method for desolvating a benzimidazole alcohol solvate comprising forming a suspension of the solvate in water. The end product is not only substantially free of alcohol it is also substantially free of water. As another example, there is cortisone acetate which precipitates from polar solvents containing less than 1% water as a hydrate. However, increasing the amount of water above 1% favors the formation of anhydrous cortisone acetate. See Carless, J. E. et. al J. Pharm. & Pharmacol.1966, 18, 190S–197S.
Processes for freeing atorvastatin hemi-calcium solvates and mixed solvates of organic solvent and water of the organic component have now been discovered.